The homeostatic chemokine, CCL17 (TARC, chemokine (C-C motif) ligand 17) is a potent lymphocyte chemoattractant. CCL17 is a ligand for CCR4, a GPCR believed to be important in the function of T cells and chemotaxis and the migration of immune cells to sites of inflammation. CCR4 is predominantly expressed on Th2 lymphocytes, natural killer cells and iNKT cells.
CCL17 has been associated with human diseases affecting various organs such as ulcerative colitis (UC), atopic dermatitis (AD), idiopathic pulmonary fibrosis (IPF) and asthma (Belperio et al., J Immunol, 173: 4692-469, 2004; Christophi et al., Inflamm Bowel Dis. doi: 10.1002/ibd.2295; Inoue et al., Eur Respir J, 24: 49-56, 2004; Kakinuma et al., J Allergy Clin Immunol, 107: 535-541, 2001; Saeki and Tamaki, J Dermatol Sci, 43: 75-84, 2006; Tamaki et al., J Dermatol, 33: 300-302, 2006). In mice, CCL17 has been linked to various inflammatory conditions and infections such as chronic pulmonary inflammation present in models of fibrosis and asthma, colitis and schistosomiasis, presumably by inducing Th2 responses through recruitment of CCR4+ immune cells. Neutralization of CCL17 ameliorates the impacts of disease in both the A. fumigatus and ovalbumin (OVA) models of asthma, and liver damage in the P. acnes mouse model of induced hepatic injury by blocking influx of T cells (Carpenter and Hogamoam Infect Immun, 73:7198-7207, 2005; Heiseke et al., Gastroenterology, 142:335-345; Hogamoam et al., Med Mycol, 43 Suppl 1, S197-202, 2005; Ismailoglu et al., Therapeutic targeting of CCL17 via the systemic administration of a monoclonal antibody ameliorates experimental fungal asthma. Paper presented at the Am J Respir Crit Care Med, 2011; Jakubzick et al., Am J Pathol, 165:1211-122, 2004; Kawasaki et al., J Immunol, 166:2055-2062, 2001; Yoneyama et al., J Clin Invest, 102:1933-1941, 1998).
CCL22 (MDC) is a second ligand for CCR4. CCR4 interaction with each chemokine produces distinct outcomes (Allen et al., Annu Rev Immunol 25:787-820, 2007; Imai et al., J Biol Chem 273:1764-1768, 1998), possibly contributed by the differences in binding affinities of the two ligands for CCR4. CCL22 binds CCR4 with higher affinity and induces receptor internalization more readily than CCL17 (Baatar et al., J Immunol 179:1996-2004, 2007; Imai et al., J Biol Chem 273:1764-1768, 1998; Mariani et al., Eur J Immunol 34:231-240, 2004), and promotes cellular adhesion more readily than CCL17 (D'Ambrosio et al., J Immunol 169:2303-2312, 2002). CCL22 shows more restricted expression with production limited to immune cells, whereas CCL17 is expressed and secreted by many different cell types including non-immune cells (Alferink et al., J Exp Med 197:585-599, 2003; Berin et al., Am J Respir Cell Mol Biol 24:382-389, 2001; Godiska et al., J Exp Med 185:1595-1604, 1997; Imai et al., J Biol Chem 271:21514-21521, 1996; Saeki and Tamaki, J Bermatol Sci 43:75-84, 2006). In the murine ceacal ligation and puncture (CLP) model of experimental sepsis, CCL22 promoted innate immunity whereas CCL17 seemed to interfere and in some circumstances contribute to organ damage (Matsukawa et al., Rev Immunogenet 2:339-358, 2000). In the mouse model of pulmonary invasive aspergillosis, CCL22 played a protective role in the innate anti-fungal response whereas CCL17 played the role of suppressor (Carpenter and Hogaboam, Infect Immun 73:7198-7207, 2005). These two chemokines can play contrasting roles in establishing localized inflammation due to differential effects on Treg homeostasis in that Treg recruitment is favored by CCL22 but not CCL17 (Heiseke et al., Gastroenterology 142:335-345, 2011; Montane et al., J Clin Invest, 121:3024-30, 2011; Weber et al., J Clin Invest 121:2898-2910, 2011).
In animal model of contact hypersensitivity, CCL17 is a major factor in initiating the inflammatory response driving contact hypersensitivity (CHS) to challenge with either FITC or DNFB, and CCL17 knockout in these mice enhanced survival of cardiac allografts compared to heterozygous mice having one functional CCL17 allele (Alferink et al., J Exp Med 197:585-599, 2003).
CCR4 antagonists may be non-selective and inhibit both CCL17 and CCL22 functions. Therefore, there is a need for anti-CCL17 antibodies for the potential treatment of a variety of CCL17-mediated diseases including asthma.